Questions
Do the INTERHEART interventions eliminate or just postpone the occurrence of cardiovascular complications?
Professor David Wood: INTERHEART, as an epidemiological study, was not an intervention trial. However, the results indicate that adopting a healthy lifestyle will reduce an individual's risk of developing myocardial infarction by 
80%. Intervention trials have shown, for example, that it is possible to reduce the risk of cardiovascular disease by blood pressure lowering or lipid lowering. These trials have been short-term, up to 6 years, because it is considered unethical to continue a clinical trial when there is a clear evidence of benefit for a given treatment. We do not know whether continuation of these treatments to over 10–15 years will simply postpone the development of atherosclerosis or eliminate the disease entirely, in other words, we will die of something else. However, the expectation from projecting the trial results is that there will be a real reduction, or prevention, of atherosclerosis.
What about the possible favourable effects of fish oil on lipids, and what about ezetimibe?
Professor Eric Bruckert: Ezetimibe is an interesting drug, which we often use in patients who do not achieve goal with either current dosage or high dosage of statins. However, we are still awaiting the results of large trials to show whether this drug reduces atherosclerosis burden.
Fish oils have almost no effect on HDL-C, LDL-C, and triglycerides at current dosages. To have an effect on triglycerides requires a very high dosage. These drugs are associated with a decrease in cardiovascular risk, but probably not through a lipid-modifying action.
Professor Wood: The mechanism is very interesting scientifically and is almost certainly related to thrombosis. However, independent of the mechanism, the evidence from GISSI-3 for fish oil supplementation following myocardial infarction is compelling in terms of reducing coronary events. Patients should be given 1 g of omega-3 fatty acids (eicosapentaenoic acid and docosahexanoic acid combined) daily.
Will statins become the aspirin of the diabetic patient?
Professor Bruckert: I think the use of statins in diabetic patients is almost mandatory, at least in the group of patients at high risk. Almost all patients with Type 2 diabetes are at high risk.
How should we screen for depression, which was a risk factor in INTERHEART?
Professor Wood: There are a number of scales that are used to assess psychological status of the patient, for example, the Hospital Anxiety and Depression Scale. These can be used to determine whether a patient is anxious or depressed and requires more support than is available through a conventional prevention programme. There is no doubt that patients who are depressed following the development of coronary disease do less well in terms of lifestyle and risk factor change than people who have come to terms with their illness. There is a close link with the social situation of the patient. It tends to be patients who are socially disadvantaged, single, who come from a poorer background and are less well educated, and so on.
The five components of the metabolic syndrome are all within the nine factors in INTERHEART. Would you advise patients with metabolic syndrome to take aspirin?
Professor Bruckert: The use of aspirin should be recommended in all patients who have a high risk, but it is not really a matter of the metabolic syndrome. If the risk of the patient is >1.5% per year, then the risk–benefit ratio of aspirin is obvious. When the risk is <1% per year, the risk–benefit ratio of aspirin is not obvious and the risk of side effects should be taken into consideration. Many patients with metabolic syndrome will have a risk that is >1.5% per year.
Why would one have to lose >10% of body weight to reduce mortality when a lesser loss will already reduce cardiovascular risk factors?
Professor Luc Van Gaal: This is a very difficult question. It mostly depends on the interaction of different risk factors that are triggering and playing together in determining the final outcome of cardiovascular disease. There is no real prospective evidence to show this. The preliminary guidelines advising 5–10% weight reduction are based on incomplete and non-prospective data.
How should we screen for the secondary causes for obesity such as Cushing's disease?
Professor Van Gaal: Cushing's disease is a metabolic and endocrine abnormality where there is not only overweight and obesity, but also a very specific abdominal fat accumulation profile with its associated co-morbidities. I advise my students that they should always screen for Cushing's disease in patients with overweight and obesity. The best way to do this is using a 24 h urinary free cortisol. You do not have to start with baseline or fasting values of plasma cortisol.
Dr Donna Ryan: One thing that is helpful in the clinic is to remember that hypothyroidism is a fairly prevalent disorder. In post-menopausal women, we screen with a TSH measurement and find 5% of undiagnosed hypothyroidism in our clinics.
Despite a large number of obese patients having diabetes, hypertension, metabolic syndrome, and so on, there are many obese people without any health problems. What should we do about the so-called healthy obese subjects?
Dr Ryan: One way of framing this is in the context of waist circumference and metabolic syndrome. An important tool in assessing individuals, particularly those with a BMI of up to 35 kg/m2, is to look at waist circumference because it adds a lot of information. Women, in particular, can be over fat without having the metabolic complications of obesity. We really need to focus on increased waist circumference and the other criteria for metabolic syndrome as being a real trigger for an intensive approach to weight reduction.
Professor Van Gaal: The most important message is that the approach for an obese individual starts with a correct assessment of risk. We have to distinguish between a medical approach to patients and a cosmetic one. The type of obesity showing an elevated BMI but a normal or near normal visceral adiposity, the gynoid type of obesity, is less dangerous and is associated with the absence of co-morbidities.
The Look AHEAD study is an ambitious project being undertaken in one of the most obesogenic environments (the US). What tips do you have for helping patients to adhere to a lifestyle modification programme?
Dr Ryan: It is surprising but analysis of the baseline data suggests that although this is an older group of patients, in terms of health-related quality of life, their scores are very high and they are highly motivated. We have set this individual goal of 10% weight loss, and so far we are very pleased with how we are doing. In terms of patient retention, we lost 1% of subjects in the first year, which is excellent. One of the things that has been insightful to me in dealing with the 350 people at my centre is some of the attitudes that they express about their physicians. I attend some of the group sessions incognito and hear them say things like ‘My doctor did not tell me that I should lose weight—he was just interested in adjusting my diabetes medication so he could bill me for his services. No one told me of the importance of weight loss with Type 2 diabetes’. The patients are enthusiastic about access to a programme that really helps direct their intervention. It is different from the Diabetes Prevention Program, in which the focus was on individual treatment; in Look AHEAD, there are three group sessions for every individual session, so there is more bonding and more cohesive groups and so far so good.
In view of the different mechanisms of actions of the different weight-reducing agents, would it be logical to combine them?
Dr Nick Finer: There have been only one or two trials of combining sibutramine and orlistat. They have not been very well designed studies; they have tended to look at adding a drug when the other has failed or reached a plateau. My own feeling, and I know that others disagree with me, is that the logic of combining sibutramine and orlistat is not very strong. One is a drug that reduces food intake and the other relies on malabsorption, so I do not think they would be additive. The likely availability of rimonabant may open up a pathway for combining with either sibutramine or orlistat in a more effective way.
Is it possible to give sibutramine with an agent such as fluoxetine?
Dr Finer: It is possible and in some parts of the world they are frequently co-prescribed. However, the datasheet for sibutramine actually forbids the combination because giving two drugs that act on central serotonergic systems increases the risk of the serotonergic syndrome, which is a serious acute medical emergency. I would concur with the datasheet that the combination is neither logical nor safe.
For how long should sibutramine be given?
Professor Arya Sharma: It has now become clear that obesity requires long-term management. From all of the data that we have seen, we know that weight regain is perhaps the most important issue in weight management. If a patient is doing well on sibutramine and is not experiencing serious side effects, if he has lost at least 5% of his body weight, then I would certainly encourage the patient to stay on the drug for as long as possible.
Dr Finer: I entirely agree, but I think we ought to be adding in to our monitoring of the clinical efficacy not just the weight loss and weight maintenance but also other factors such as HDL-cholesterol, glycaemic control, and so on.
As a cardiologist with patients similar to those entered into the SCOUT trial, the average number of drugs my patients are on is anything from 6 to 13. Is there any information on drug–drug interactions with sibutramine?
Professor Sharma: I am not too concerned about interactions of sibutramine with cardiovascular drugs, but of the 13 drugs your patients are on they are also likely to be on an antidepressant, and the mode of action of that drug is very similar to the mode of action of sibutramine. In principle, I would not think there would be an interaction with sibutramine, although as Dr Finer has pointed out, we should be careful about combining sibutramine with an SSRI. We need to avoid this, as the serotonergic syndrome is very serious.
Dr Ryan: In the US, the FDA has now allowed, in the prescribing information for sibutramine, that the drug can be used with SSRIs. It is still cautioned, but there have been no documented cases of serotonergic syndrome with sibutramine. The drug is, however, contraindicated with the use of MAO-inhibitors.
If the blood pressure actually falls with sibutramine, does it need monitoring?
Professor Sharma: There is a small group of patients that seems to be extremely susceptible to an increase in blood pressure. Although the likelihood of seeing a marked increase in blood pressure with sibutramine is extremely rare, it is important to find those patients and to take them off of the drug or at least to monitor them and ensure they are not becoming hypertensive. So yes, blood pressure does need to be monitored.
Why are anti-obesity drugs so expensive?
Professor Sharma: These drugs are no more expensive than statins or many other new agents that are on the market. What makes them expensive for the patient is that they are not reimbursed by many health care systems. In Canada, every time we apply for coverage for these drugs, we are told that it has been shown that tolerance develops to the drugs. This concept is nonsense, but it reflects the bias and discrimination against obesity as a serious medical condition that warrants long-term treatment.
Dr Finer: In the UK, they are reimbursed because the National Institute for Clinical Excellence (NICE) deemed that they easily pass the threshold for cost-efficacy.
Bariatric surgery is now very much improved. Is this a more realistic option for very obese patients?
Dr Finer: Paradoxically, in the UK, although we can get reimbursement for sibutramine and orlistat, there is virtually no funding for bariatric surgery, which is now relatively inaccessible. You are right to highlight the fact that for morbidly obese patients, those with a BMI of 40–50 kg/m2, surgery is becoming an increasingly viable and acceptable intervention. It seems to me that we should be using pharmacotherapy more in the middle ground—we should be using it earlier in patients who have not yet become refractorily obese. Whether you wait for diet to fail or whether you prescribe a programme that recognizes that patients do benefit from having drugs as the clinical trials show will depend on your circumstances. My approach is not to give drugs only when everything else has failed but, quite the reverse, to use drugs as a part of the initial management system.
Professor Sharma: Part of the philosophy that we have to start moving towards when we think of the pharmacological treatment of obesity is to prevent morbid obesity. When you have a patient with a BMI of 35 kg/m2 you do not want him to get a BMI of 40 kg/m2 and to need surgery. The issue, as Dr Finer says, is that we should step in early with our pharmacological treatment not just to get the benefit of the treatment but also to prevent a disease that is even more disabling, that is morbid obesity. The Ontario health assessment unit has recently published a report concluding that bariatric surgery is not only effective but also cost-effective. Currently, Ontario sends 600 people a year to the US for surgery. They have now decided that for that money they could perform 1400 operations a year in Ontario. They have calculated that they need about 4500 operations a year to cover current requirements. The consensus now is that for most patients who do not have strict contraindications, bariatric surgery is something that needs to be discussed.
How can we help patients to accept that they only need to lose 5–10% of their body weight when they want to lose much more and how do we help them to comply with weight management?
Professor Leif Erhardt: I can only answer from the perspective of managing patients with various cardiac disorders. I think the first thing people ask themselves is ‘What is in it for me?’ When it comes to obesity, there is the advantage that patients can see when they lose weight, they can measure it easily at home, and they feel better immediately. These are bonuses additional to the benefits in cardiovascular risk factors. Therefore, I think that when it comes to giving advice about losing weight, communicating about the benefits of losing weight together with the other risk factors is important. To me it has been a revelation to learn that there are so many other things associated with losing weight, such as reducing blood pressure and also reducing sympathetic tone, both of which we know are adding to cardiovascular risk. I think that in future, we have to bring obesity into the risk algorithms and try to communicate about what body weight does for you in relation to other risk factors.
For which patients would you prescribe sibutramine?
Dr Finer: The datasheet for the drug certainly should guide our prescribing of sibutramine. Working in a hospital-based special clinic, I rarely see patients with a BMI <30 kg/m2. But in terms of primary care, I would advise that if you have a patient with a BMI of 25 kg/m2, they are pre-obese and therefore they should be considered for treatment, particularly if they have other risk factors.
In view of the effect of sibutramine on heart rate and blood pressure, is it possible to give it together with a beta-blocker?
Professor Sharma: This has been studied in two clinical trials and there is no doubt that you can block the tachycardic effect of sibutramine with a beta-blocker. However, another study has shown that increasing physical activity can also counteract the increase in heart rate that is seen with sibutramine. Physical activity is certainly something that needs to be part and parcel of any weight loss programme. The evidence is that physical activity will decrease sympathetic activity and reduce heart rate so you do not have to go straight to the beta-blocker.
What is the effect of sibutramine on binge eating if it has this satiety effect?
Professor Sharma: Binge eating is the only cause of obesity where there is evidence that cognitive behavioural therapy works. If you run an obesity clinic, you want to be very particular about identifying the binge eaters because you may want to send them for behavioural therapy. That said, that there are data showing that sibutramine works in binge eaters, and also recent data showing that surgery is effective in binge eaters. However, binge eaters are a minority of the morbidly obese population; most people are not obese because they binge.
Dr Finer: I agree with that and would add that just as we should be using scoring systems for cardiovascular risk, there is much to be said for using some of the standard questionnaires for assessing binge eating or abnormal eating behaviours in patients who present with obesity.
When will we have the final results of SCOUT?
Professor Philip James: On the basis of the current analyses, we should have the final results in the second half of 2008.
Conflict of interest: All speakers have lectured at Abbott-sponsored symposia.
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